Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, chronic and acute pain.
The compounds of formula I: 
and their salts are distinguished by valuable therapeutic properties. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, the manufacture of such medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier, and, respectively, for the manufacture of corresponding medicaments.
The present invention relates to compounds of formula I: 
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, nitro, cyano, lower alkyl-amino, di-lower alkyl-amino or halogen;
R2 is phenyl, optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, lower alkyl-amino or di-lower alkyl-amino, 2,3-dihydro-benzofuran-5-yl, chroman-6-yl, naphthalen-2-yl, indan-5-yl, lower alkenyl-phenyl, 5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-isoindol-2-yl, 1,2,3,4-tetrahydro-naphthalenyl, benzofuran-2-yl, benzo[b]thiophen-2-yl, lower alkyl-phenyl, 3,4-dihydro-1H-isoquinolin-2-yl or thiophen-3-yl;
R3 and R4 are independently from each other hydrogen or lower alkyl;
R5 is hydrogen, lower alkyl, xe2x80x94CH2OH or xe2x80x94CH2NR6R7;
R6 and R7 are independently from each other hydrogen, lower alkyl, xe2x80x94(CH2)n-phenyl, cycloalkyl, xe2x80x94(CH2)m-morpholinyl or form together with the N-atom a saturated ring with 4-6 C-atoms;
n is 0-3;
m is 2 or 3;
X is xe2x80x94NR8xe2x80x94 or xe2x80x94Oxe2x80x94; or
X and R5 are together  greater than N(CH2)2xe2x80x94; or
X and R3 are together  greater than N(CH2)3xe2x80x94; and
R8 is hydrogen or lower alkyl;
and to pharmaceutically acceptable acid addition salts thereof.
Not encompassed from compounds of formula I are the following specific compounds, which are described in Indian Journal of Chemistry, Vol. 35B, 1996, 871-873 and having an antibacterial activity.
(6-Chloro-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol;
(6-methyl-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol;
(6-methoxy-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol; and
(8-methoxy-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol;
The present invention embraces racemic mixtures and all their corresponding enantiomers.
The following definitions of the terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
The term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residue is as defined above.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I in the scope of the present invention are those, wherein X is xe2x80x94NHxe2x80x94 and R5 is hydrogen, xe2x80x94CH2NH2, xe2x80x94CH3 or xe2x80x94CH2OH. These are the following compounds:
2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-4-ylamino]-ethanol,
(RS)-1-amino-3-(2-p-tolyl-quinolin-4-ylamino)-propan-2-ol,
(RS)-1-amino-3-[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol,
S(+)-1-[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol,
2-[2-(4-methoxy-phenyl)-7-methyl-quinolin-4-ylamino]-ethanol,
(S)-1-[2-(4-methoxy-3-methyl-phenyl)-quinolin-4-ylamino]-propan-2-ol,
2-(7-Methyl-2-p-tolyl-quinolin-4-ylamino)-ethanol,
(S)-1-[2-(3-chloro-4-methyl-phenyl)-quinolin-4-ylamino]-propan-2-ol,
(RS)-3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-4-ylamino]-propane-1,2-diol,
RS)-1-amino-3-[2-(3,4-dihydro-1H-isoqulinolin-2-yl)-quinolin-4-ylamino]-propan-2-ol,
2-[7-methoxy-2-(4-methoxy-phenyl)-quinolin-4-ylamino]-ethanol,
(RS)-1-amino-3-[7-methoxy-2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol or
(RS)-1-amino-3-(7-methoxy-2-p-tolyl-quinolin-4-ylamino)-propan-2-ol.
Compounds of the present invention, in which X is xe2x80x94Oxe2x80x94 and R5 is xe2x80x94CH2NHCH3, xe2x80x94CH2NH2, xe2x80x94CH2NHCH(CH3)2 or xe2x80x94CH2NH-cycloalkyl, are further preferred, for example the following compounds:
(RS)-1-(7-methoxy-2-phenyl-quinolin-4-yloxy)-3-methylamino-propan-2-ol,
(RS)-1-amino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-isopropylamino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-cyclopentylamino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-isopropylamino-3-(7-methoxy-2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-methylamino-3-(2-p-tolyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-cyclobutylamino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-[2-(4-methoxy-phenyl)-quinolin-4-yloxy]-3-methylamino-propan-2-ol,
(RS)-1-methylamino-3-(7-methyl-2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-(7-methoxy-2-p-tolyl-quinolin-4-yloxy)-3-methylamino-propan-2-ol,
(RS)-1-[7-methoxy-2-(4-methoxy-phenyl)-quinolin-4-yloxy]-3-methylamino-propan-2-ol or
(RS)-1-[2-(4-methoxy-phenyl)-7-methyl-quinolin-4-yloxy]-3-methylamino-propan-2-ol.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a compound of formula: 
xe2x80x83with an amine of formula: 
xe2x80x83to a compound of formula: 
xe2x80x83wherein R1-R5 and R8 have the significances given above, or
b) reducing a compound of formula: 
xe2x80x83with a reducing agent to a compound of formula: 
xe2x80x83wherein R1-R4 and R8 have the significances given above, or
c) reducing a compound of formula: 
xe2x80x83wherein R1-R4 and R8 have the significances given above and R6 is lower alkyl-phenyl, lower alkyl-morpholino or lower alkyl,
xe2x80x83to a compound of formula: 
xe2x80x83or
(d) reacting a compound of formula: 
xe2x80x83with a compound of formula: 
xe2x80x83to a compound of formula: 
xe2x80x83wherein R1-R4 and R6 have the significances given above, or,
e) reacting a compound of formula: 
xe2x80x83with a compound of formula:
Hxe2x80x94NR6
xe2x80x83to a compound of formula: 
xe2x80x83wherein R1-R4 and R6 have the significances given above, or,
xe2x80x83if desired, modifying one or more substituients within the definitions given above, or
xe2x80x83if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.
In the following the preparation of compounds of formula I are described in more detail:
1. Preparation of Compounds of Formula I, wherein X is xe2x80x94NR8xe2x80x94
The amino group in 4-position is introduced using known procedures1, for example by reaction at 150xc2x0 C. of a corresponding 4-chloro-quinoline with a primary or secondary amine using the neat amine as solvent (scheme 1).
1Field, G. F.; Zally, W. J. (Hoffman-La Roche, Inc., USA). U.S. Pat. No. 4,560,692 
Introduction of the methyl or higher alkyl groups on the primary group of the side chain was performed using known methods by reduction of an oxazolidin-2-one or an amide (scheme 1). Compounds carring a phenethyl substituents at the 2-position were prepared by hydrogenation of the corresponding styryl derivatives.
2. Preparation of Compounds of Formula I, wherein X is xe2x80x94Oxe2x80x94 
Compounds were made using known procedures either by reacting an amine with an epoxide or by reacting an oxazolidine with a 4-chloro-quinoline in the presence of sodium hydride2. Epoxides were prepared using a known procedure by reacting a quinolin-4-one with a chloro epoxide3 (scheme 2).
2Baldwin, J. J.; Lumma, W. C., Jr.; Lundell, G. F.; Ponticello, G. S.; Raab, A. W.; Engelhardt, E. L.; Hirschmann, R.; Sweet, C. S.; Scriabine, A.; J. Med. Chem. (1979), 22(11), 1284-1290. 
3Asthana, P.; Prasad, M.; R., Shri N.; Indian J.Chem.Sect.B; 26; 1987; 330-334 
3. Preparation of the Intermediates of Formula II 
2-Amino-4-chloro-quinoline have been prepared by reacting of 2,4-dichloro-quinoline with a dialkylamine in refluxing toluene. This reaction was found to be completely regioselective (scheme 3).
Known procedures have been used:
by adding an aryl or heteroaryl lithium to a 4-chloro-2-unsubstituted-quinoline followed by treatment with an oxidant like iodine1 
by converting a quinolin-4-one to the corresponding 4-chloro derivative in the presence of a chlorinating agent like phosphorus oxychloride1 
1Field, G. F.; Zally, W. J. (Hoffmann-La Roche, Inc., USA). U.S. Pat. No. 4,560,692 
By known procedure has been used reaction of a 2-methyl-4-chloro-quinoline with benzaldehyde.2 
2I. G. Farbenind.; DE 440008 
By reaction of methoxy substituted-4-chloro-quinoline with BBr3.
Known procedures have been used
by condensation of an aniline with a xcex2-ketoester4 or
by condensation of derivatives of anthranilic acid and aceto phenones5.
4Hauser, C. R.; Reynolds, G. A.; J. Am. Chem. Soc. 1948,70, 2402; Hauser, C. R.; Murray, J. G.; J. Am. Chem. Soc. 1955,77, 2851. 
5Jones G.; Quinolines, The Chemistry of Heterocyclic Compounds, Vol 32, Wiley, N.Y., 1977, 181-191, 195-207 
Pharmaceutically acceptable salts can be manufactured according to methods which are known per se and familiar to any person skilled in the art. The acid addition salts of compounds of formula I are especially well suited for pharmaceutical use.
In schemes 1-3 are described processes for preparation of compounds of formula 1, starting from known compounds, from commercial products or from compounds, which can be prepared in conventional manner.
The preparation of compounds of formula I are described in more detail in working examples 1-103.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable acid addition salts possess valuable pharmacodynamic properties. They are NMDA-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
The compounds were investigated in accordance with the test given hereinafter.
Test method
Male Fxc3xcllinsdorf albino rats weighing between 150-200 g were used. Membranes were prepared by homogenization of the whole brain minus cerebellum and medulla oblongata with a Polytron (10 000 rpm, 30 seconds), in 25 volumes of a cold Tris-HCl 50 mM, EDTA 10 mM, pH 7.1 buffer. The homogenate was centrifuged at 48.000 g for 10 minutes at 4xc2x0 C. The pellet was resuspended using the Polytron in the same volume of buffer and the homogenate was incubated at 37xc2x0 C. for 10 minutes. After centrifugation the pellet was homogenized in the same buffer and frozen at xe2x88x9280xc2x0 C. for at least 16 hours but not more than 10 days. For the binding assay the homogenate was thawed at 37xc2x0 C., centrifuged and the pellet was washed three times as above in a Tris-HCl 5 mM, pH 7.4 cold buffer. The final pellet was resuspended in the same buffer and used at a final concentration of 200 mg of protein/ml.
3H-Ro 25-6981 binding experiments were performed using a Tris-HCl 50 mM, pH 7.4 buffer. For displacement experiments 5 nM of 3H-Ro 25-6981 were used and non specific binding was measured using 10 mM of tetrahydroisoquinoline and usually it accounts for 10% of the total. The incubation time was 2 hours at 4xc2x0 C. and the assay was stopped by filtration on Whatmann GF/B glass fiber filters (Unifilter-96, Packard, Zxc3xcrich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the filter was counted on a Packard Top-count microplate scintillation counter after addition of 40 mL of microscint 40 (Canberra Packard S.A., Zxc3xcrich, Switzerland).
The effects of compounds were measured using a minimum of 8 concentrations and repeated at least once. The pooled normalized values were analyzed using a non-linear regression calculation program which provide IC50) with their relative upper and lower 95% confidence limits (RS1, BBN, USA).
The IC50(xcexcM) of preferred compounds tested in accordance with the above mentioned methods are in the range of about 0.01-0.15.
In the table below are given some IC50 (xcexcM) for preferred compounds:
The compounds of formula I and their salts, as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application with the usual pharmaceutical adjuvant materials, for example, organic or inorganic inert carrier materials, such as, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in the range of about 0.1 mg per dosage to about 1000 mg per day of a compound of formula I although the upper limit can also be exceeded when this is shown to be indicated.